title: Oxidatively activated DNA-modifying agents for selective cytotoxicity.
abstract: DNA-modifying agents are stalwarts of chemotherapeutic cancer treatments, but require significant design improvements to improve selectivity, minimize side effects, and for their widespread use to continue. Herein we present a novel design strategy in which DNA-modifying agents contain an oxidizable leaving group and a nitrogen mustard. The agents form strong electrophiles specifically when oxidized. Activation, measured by hydrolysis, illustrates that oxidants increase reactivity 1700-fold. Reaction in the presence of 2'-deoxyguanosine leads to the formation of lesions. Cytotoxicity measured in HeLa cells showed that low IC(50) values require an oxidizable hydroquinone and a nitrogen mustard fragment. Cytotoxicity measurements in 15 cancer cell lines demonstrates that oxidatively activated DNA-modifying agents are highly selective, as the analogue tested has IC(50) values less than 10 μM for only three of the 15 cell lines; in contrast, cisplatin is highly toxic to 13 of the 15 cell lines. The selective cytotoxicity of oxidatively activated DNA-damaging agents could be useful against kidney cancer cells, as the 786-O cell line model assay resulted in an IC(50) value of 5 μM.
authors.affiliation: Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221-0172, USA.
authors.forename: Guorui
authors.initials: G
authors.lastname: Li
authors.forename: Tiffany
authors.initials: T
authors.lastname: Bell
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Merino
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D017209:Apoptosis; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D003849:Deoxyguanosine / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D006873:Hydroquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D010084:Oxidation-Reduction
chemical_list: D000970:Antineoplastic Agents; D006873:Hydroquinones; D004247:DNA; D003849:Deoxyguanosine; C031927:hydroquinone